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INTERNATIONAL JOURNAL OF REVIEW ARTICLE PHARMACEUTICAL INNOVATIONS ISSN 2249-1031

25 | P a g e Volume 3, Issue 5, September ₋ October 2013 http://www.ijpi.org

A REVIEW ON CO-PROCESSED EXCIPIENTS: A NOVEL APPROACH IN

FORMULATION DEVELOPMENT

Patil Atul1*; Kundu Subrata2; Srinivasan Ganga3

Shri JJT University, Rajasthan1

VerGo Pharma Research Laboratories Pvt. Ltd, Goa2

Vivekananda College of Pharmacy, Mumbai University3

ABSTRACT:

Co-processed excipients help to overcome the deficiencies occurring with the use of general

grade excipients. The co-processed excipients retain favourable attributes, and are

supplemented with new ones. As the chemical change is absent, they are considered to retain

the “GRAS” (Generally Regarded as Safe) status. Co-processed excipients are believed to

bring a drastic change in the field of pharmaceutical Research.

Keywords: Co-processing, Adjuvant, excipients, Novel drug delivery system.

INTRODUCTION:

In recent years scientists have found out

that single-component excipients do not

always provide the requisite performance

to allow certain active pharmaceutical

ingredients to be formulated or

manufactured. Hence formulation

scientists have worked on combination of

excipients to overcome the deficiencies

occurring with the use of general grade

excipients.

There is considerable activity in the

development of new and innovative

excipients. Excipient Innovations include

excipients for orally disintegrating tablets

and controlled-release formulations. New

technologies are being evaluated to

increase the amount or rate of absorption

of drugs with new excipients. In the future,

the application of nanotechnology may be

evaluated for developing novel excipients

for new therapeutic solutions.

Co-Processed Excipients Enhanced

Performance [1]

- Combination (“intimate” mixtures)

of established excipients that

possess performance advantages

and improvements: increased

surface area, improved flow,

compaction, etc.

- Covalent bonds usually not formed

- High-functionality excipients

(perform multiple functions)

- Produced using specialized

manufacturing process: high shear

dispersion, granulation, spray

drying, melt extrusion

- One or more components may be

formed in situ

*Corresponding Author

Patil Atul



- Appropriate for monograph

consideration in the United States

Pharmacopeia/National Formulary

- Several listed in FDA Inactive

Ingredient Database

- May create new intellectual

property

Combination excipients are of two types:

physical mixtures and co-processed

excipients. [2]

A co-processed excipient is a

combination of two or more excipients

having physically modified their properties

in a manner not achievable by simple

physical mixing, and without significant

change in the chemical properties. Co-

processed microcrystalline cellulose and

calcium carbonate were the first co-

processed excipients (1980). It was

followed by Cellactose (Meggle Corp.,

Wasserburg, Germany) in 1990, [3]

which

is a co-processed combination of cellulose

and lactose. Later, silicified

microcrystalline cellulose (SMCC), which

is the most widely used co-processed

excipient was developed using the same

technique and many more in the recent

years. [4]

Excipients:

Pharmaceutical excipients are substances

other than the API which have been

appropriately evaluated for safety and are

intentionally included in a drug delivery

system. For example, excipients can:

Aid in the processing of the drug

delivery system during its manufacture,

Protect, support or enhance stability,

bioavailability or patient acceptability,

Assist in product identification, or

Enhance any other attribute of the

overall safety, effectiveness or delivery

of the drug during storage or use.

Types of Excipients

1. Standard Excipients

Standard excipients are defined as

compendial or non-compendial substances

that are neither mixed excipients nor co-

processed excipients. They may contain

other components including concomitant

components, residual processing aids

and/or additives.

2. Mixed Excipients

A mixed excipient is defined as a simple

physical mixture of two or more

compendial or non-compendial excipients

produced by means of a low- to medium-

shear process where the individual

components are mixed but remain as

discrete chemical entities, i.e. the nature of

the components is not chemically

changed,. Mixed excipients may be either

solid or liquid.

3. Co-processed Excipients

A co-processed excipient is a combination

of two or more compendial or non-

compendial excipients designed to

physically modify their properties in a

manner not achievable by simple physical

mixing, and without significant chemical

change. Many different co-processing

methods may be used, including standard

unit operations such as granulation, spray

drying, melt extrusion, milling etc. The

choice for a specific application will

depend on the materials used, their form

(e.g. whether dry powders or liquid) and

the specific physical properties desired.

Likewise the ratios of the components may



vary depending on the desired

performance. [5]

Co-processing is a novel concept in which

the excipient functionality is altered by

retaining the favorable attributes and

supplementing with newer-ones. This is

achieved by processing the parent

excipient with another excipient. This

allows production of high-functionality

excipients which can be of a greater

importance to the formulator. The high

functionality can be in terms of improved

process ability such as flow properties,

compressibility, content uniformity,

dilution potential, and lubricant sensitivity,

or improved performance such as

disintegration and dissolution profile. [6]

Need For Co-Processed Excipients:

It has been found that less than 20 per cent

of pharmaceutical materials can be

compressed directly into tablets due to lack

of flow, cohesion properties and

lubrication. Therefore, they must be

blended with other directly compressible

ingredients to manufacture satisfactory

tablets. In the development of directly

compressible granules by the modification

of a single substance, Co-processing

involves interaction of two or more

excipients at the sub-particle level, aimed

at providing a synergy of functionality

improvements, as well as masking the

undesirable properties of the individual

excipients. The composite particles or

co‐processed multi‐component‐based

excipients are introduced to achieve better

powder characteristics and tableting

properties than a single substance or the

physical mixture.

The availability of a large number of

excipients for co-processing provides a

plethora of opportunities to produce tailor

made „„designer excipients‟‟ catering to

specific functionality requirements.[7]

The

combination of excipients chosen for co-

processing should complement each other

to mask the undesirable properties of

individual excipients and at the same time,

retain or improve the desired properties of

excipients. For example, if a substance

used as a filler–binder has a low

disintegration property, it can be co-

processed with another excipient that has

good wetting properties and high porosity

because these attributes will increase the

water intake, which will aid and increase

the disintegration of the tablets.[8]

Difference between physical mixtures

and co-processed excipients

Physical mixtures, as the name suggests,

are simple admixtures of two or more

excipients typically produced by short

duration low-shear processing. They may

be either liquids or solids and are generally

used for convenience rather than for

facilitating the manufacturing process or

improving the resultant pharmaceutical

product. [9]

Co-processed excipients are combinations

of two or more excipients that possess

performance advantages that cannot be

achieved using a physical admixture of the

same combination of excipients. Typically

they are produced using some form of

specialized manufacturing process. The

performance benefits relate to the

manufacture or performance of the

finished pharmaceutical product. [9]

Co-

processed excipients are appropriate for

consideration as new monographs because

one or more of the components may be



formed in situ, or the component may not

be isolated prior to co-processing [6]

PROCESS OF DEVELOPING CO-

PROCESSED EXCIPIENTS:

The actual process of developing a co-

processed excipient involves the following

steps:

1. Identification of the group of

excipients to be co-processed: This is

done by taking material characteristics and

functionality requirements into

consideration.

2. Selection of proportion of various

excipients

3. Assessing the particle size: This is

important because, Post processing the

particle size of the latter depends on its

initial particle size.

4. Selecting a suitable process of drying:

processes such as spray- or flash drying

are employed

5. Optimizing the process (because even

this can contribute to functionality

variations. [6]

Figure 1: Demonstrating the co-processing technology



Considering material characteristics in

co-processing:

Material science plays an important role in

altering the physical and mechanical

characteristics of a material, especially

with regard to its compression and flow

behaviour. [10]

Materials can be classified

as elastic, plastic, or brittle materials by

virtue of their response to applied forces.

Pharmaceutical materials exhibit all three

types of behavior, with one type being the

predominant response. This makes it

difficult to demarcate which property is

good for compressibility. Co-processing is

generally conducted with one excipient

that is plastic and another that is brittle.

Scientists have experimented to make co-

processed excipients by utilizing large

amount of brittle material and a small

amount of plastic material, as exemplified

by Cellactose (Meggle Corp.) in which

75% lactose (brittle material) is co-

processed with 25% cellulose (plastic

material).[11]

This combination prevents

the storage of too much elastic energy

during compression, which results in a

small amount of stress relaxation and a

reduced tendency of capping and

lamination.[12]

However, examples of the

other extreme also exist (e.g., SMCC has a

large amount of MCC [plastic material]

and a small amount of silicon dioxide

[brittle material]).[13]

A combination of

plastic and brittle materials is necessary for

optimum tableting performance. Hence,

co-processing these two kinds of materials

produces a synergistic effect, in terms of

compressibility, by selectively overcoming

the disadvantages. These types of

combinations help in improving

functionalities such as compaction

performance, flow properties, strain-rate

sensitivity, lubricant sensitivity or

sensitivity to moisture, or reduced

hornification. [14]

Advantages of co-processed excipients

1. Improved flow properties:

Controlled particle-size distribution and

optimum particle size ensures superior

flow properties of co-processed excipients

without the need of using glidant. Consider

the volumetric flow properties of SMCC

(silicified micro crystalline cellulose) were

studied in comparison with MCC. The

particle-size range of co-processed and

parent excipients was similar but the flow

of co-processed excipients was better than

the flow of simple physical mixtures. [15]

A

comparison of the flow properties of

Cellactose and lactose was also performed.

Cellactose was found to have better flow

characteristics than lactose or a mixture of

cellulose and lactose. The spray-dried

product had a spherical shape and even

surfaces, which also improved the flow

properties. [16]

2. Improved compressibility:

Co-processed excipients have been used

mainly in direct-compression tableting

because in this process there is a net

increase in the flow properties and

compressibility profiles and the excipient

formed is a filler–binder. The pressure–

hardness relation of co-processed

excipients, when plotted and compared

with simple physical mixtures, showed a

marked improvement in the

compressibility profile. The

compressibility performance of excipients

such Cellactose [17]

, SMCC [18]

, and

Ludipress have been reported to be



superior to the simple physical mixtures of

their constituent excipients. SMCC

retained its compaction properties even at

high compression forces, yielding tablets

of good hardness. [19]

MCC, however, lost

its compaction properties. Although direct

compression seems to be the method of

choice for pharmaceutical manufacturing,

wet granulation is still preferred because it

has the potential advantages of increasing

flow properties and compressibility when

an extra granular binder is introduced, and

it achieves a better content uniformity in

case of low-dose drugs. Excipients such as

MCC lose compressibility upon the

addition of water, a phenomenon called

quasi hornification. This property is

improved, however, when it is co-

processed into SMCC.

3. Better Dilution potential:

Dilution potential is the ability of the

excipient to retain its compressibility even

when diluted with another material. Most

active drug substances are poorly

compressible, and as a result, excipients

must have better compressibility properties

to retain good compaction even when

diluted with a poorly compressible agent.

Cellactose is shown to have a higher

dilution potential than a physical mixture

of its constituent excipients. [20]

4. Fill weight variation:

In general, materials for direct

compression tend to show high fill-weight

variations as a result of poor flow

properties, but co-processed excipients,

when compared with simple mixtures or

parent materials, have been shown to have

fewer fill-weight variation problems. The

primary reason for this phenomenon is the

impregnation of one particle into the

matrix of another, which reduces the rough

particle surfaces and creates a near-optimal

size distribution, causing better flow

properties. Fill-weight variation was

studied with various machine speeds for

SMCC and MCC, and SMCC showed less

fill-weight variation than MCC. [21]

5. Reduced lubricant sensitivity

Most co-processed products consist of a

relatively large amount of brittle material

such as α-lactose monohydrate and a

smaller amount of plastic material such as

cellulose that is fixed between or on the

particles of the brittle material. The plastic

material provides good bonding properties

because it creates a continuous matrix with

a large surface for bonding. The large

amount of brittle material provides low

lubricant sensitivity because it prevents the

formation of a coherent lubricant network

by forming newly exposed surfaces upon

compression, thus breaking up the

lubricant network. [22]

Other advantages:

(a) Pharmaceutical manufacturers have

the option of using a single excipient

with multiple functional properties,

thereby reducing the number of

excipients.

(b) Improved organoleptic properties

such as those in Avicel CE-15 (FMC

Corp., Philadelphia, PA), which is a

co-processed excipient of MCC, and

guar gum were shown to have

distinctive advantages in chewable

tablets in terms of reduced grittiness,

reduced tooth packing, minimal

chalkiness, better mouth feel, and

improved overall palatability in

inventory.



(c) Overall product cost decreases

because of improved functionality

and fewer test requirements

compared with individual excipients.

(d) Co-processed excipients can be used

to develop tailor-made designer

excipients. This can be helpful in

reducing the time required to

develop formulations.

(e) Co-processed excipients can be used

as proprietary combinations, and in-

house formularies can be maintained

by pharmaceutical companies could

help in developing a formulation that

is difficult to reproduce and provides

benefits in terms of intellectual

property rights. [23]

Limitations of co-processed excipients:

Major limitation of co-processed excipient

mixture is that the ratio of the excipients in

a mixture is fixed and in developing a new

formulation, a fixed ratio of the excipients

may not be an optimum choice for the API

and the dose per tablet under development.

Co-processed adjuvant lacks the official

acceptance in pharmacopoeia. For this

reason, a combination filler/binder will not

be accepted by the pharmaceutical industry

until it exhibits significant advantages in

the tablet compaction when compared to

the physical mixtures of the excipients.

Although the spray-crystallized dextrose-

maltose (Emdex) and compressible sugar

are co-processed products, they are

commonly considered as single

components and are official in USP/NF.

CO-PROCESSED DIRECTLY

COMPRESSIBLE ADJUVANTS

Ludipress:

Ludipress, a co-processed product, consists

of 93.4% α- lactose monohydrate, 3.2%

polyvinyl pyrrolidone (Kollidon 30) and

3.4% crospovidone (Kollidon CL). [24]

It

consists of lactose powder coated with

polyvinyl pyrrolidone and crospovidone.

At low compression force Ludipress gives

harder tablets but the addition of glidant

and disintegrant is needed. It is reported

that binding capacity of Ludipress was

higher than that of microcrystalline

cellulose. The dilution potential was high

(up to 70%) when aspirin was used a

model drug [25]

. The binding property of

Ludipress, both un-lubricated and

lubricated with 1% magnesium stearate

was found to be much better than

corresponding physical mixture. The

disintegration time of Ludipress containing

tablets remained unchanged at about 100

MPa compaction pressure while significant

prolongation was observed with

Cellactose. Ludipress exhibited highest

flow ability followed by Cellactose,

Tablettose, Fast Flo lactose and anhydrous

lactose as demonstrated by lower static and

dynamic angles of repose than the other

excipients. The values of compressibility

could be ranked from maximum to

minimum in the following order:

Tablettose, Cellactose, Ludipress and Fast

Flow lactose. Fragmentation propensity

was from maximum to minimum in

Tablettose, Cellactose, Ludipress and Fast-

Flo lactose. [26]

Cellactose:

Cellactose is a co-processed product

consisting α-lactose monohydrate (75%)

and cellulose (25%). Apart from good flow

ability, it has good compatibility. [27]

The

compatibility is attributed to a synergetic

effect of consolidation by fragmentation of

lactose and plastic deformation of



cellulose. Because the lactose covers the

cellulose fibers, moisture sorption is much

lower than that of microcrystalline

cellulose alone. Armstrong et al. pointed

that Cellactose exhibit the dual

consolidation behavior since it contains a

fragmenting component (Lactose) and a

substance that consolidates primarily by

plastic deformation (Cellulose). It was

reported that the Cellactose exhibited

better compressibility compared to

Ludipress, Fast Flo lactose, Tablettose, Di-

pac and anhydrous lactose.[28]

Belda and

Mielck found that due to co-processing

Cellactose exhibited enhanced crushing

strength compared to the powder mixtures

each containing 25% w/w Avicel PH-101

or Elcema P-100 and 75% w/w Tablettose

or lactose (100#). Casal derrey et al

reported that the Cellactose tablets

prepared at a compression pressure that

largely eliminated macro pores had better

mechanical properties but much poorer

disintegration than tablets of the other

blends having similar composition, particle

size, and true density at the same punch

pressure. Authors further reported that the

tensile strength and disintegration time of

Cellactose tablets decreased rapidly as the

compression pressure is reduced.

Goheland Jogani prepared and evaluated

co-processed directly compressible

adjuvant containing lactose and

microcrystalline cellulose using starch as a

binder. The percentage fines, Carr‟s index

of the agglomerates as well as friability

and tensile strength of the tablets were

affected by the ratio of lactose to

microcrystalline cellulose and percentage

of starch in binder solution. A product

containing lactose: microcrystalline

cellulose (9:1) and 1% starch paste

exhibited satisfactory flow,

compressibility and friability. Tablets of

diltiazem hydrochloride and

acetaminophen prepared using the co-

processed excipients exhibited satisfactory

tableting properties. Gohel et al. prepared

and evaluated co-processed diluents

containing lactose and microcrystalline

cellulose using a 23 factorial design. Ratio

of lactose to MCC (75: 25 and 85:15), type

of binder (hydroxypropyl methylcellulose

or dextrin) and binder concentration (1 or

1.5%) were studied as independent

variables. The results revealed that the

lactose: microcrystalline cellulose ratio

75:25 and dextrin as a binder are better

than the ratio of 85:15 and

hydroxypropylmethylcellulose as a binder.

The tableting properties of the developed

adjuvant were ascertained using diltiazem

HCl as a model drug. Gohel and Jogani

prepared co-processed directly

compressible adjuvant containing lactose

and microcrystalline cellulose using melt

granulation technique. Gohel et al

demonstrated use of factorial design in

development of directly compressible

adjuvant of desired characteristics

consisting of lactose, dicalcium phosphate

and microcrystalline cellulose.

Pharmatose DCL 40

It is a co-processed product consisting of

95% β-lactose and 5% anhydrous lactitol.

Due to spherical shape and favorable

particle size, it exhibits good flow ability.

It has high dilution potential than other

lactose based products due to better

binding property. It has very low water

uptake at high humidity. [29]



Prosolv

It is co-processed silicified

microcrystalline cellulose. It consists of

98% microcrystalline cellulose and 2%

colloidal silicone dioxide. The

manufacturer claim better flow ability and

compressibility compared to Emcocel and

Avicel PH 101 or physical mixture of

MCC with colloidal silicone dioxide.

Allen reported that Prosolv containing

tablets were significantly robust than those

produced from regular cellulose by wet

granulation. In the presence of magnesium

stearate (0.5%), tablets prepared with

Prosolv maintained tensile strength

profiles, whereas the tensile strength of

regular cellulose was significantly

affected. Author further Prosolv containing

tablets were significantly robust than those

produced from regular cellulose by wet

granulation. In the presence of magnesium

stearate (0.5%), tablets prepared with

Prosolv maintained tensile strength

profiles, whereas the tensile strength of

regular cellulose was significantly

affected. Author further reported that

Prosolv is about 20% more compactable

than regular cellulose. Fraser et al reported

that silicified microcrystalline cellulose

has some improvement in flow but

considerably enhanced mechanical

properties. Lahdenpera et al. demonstrated

that Silicified microcrystalline cellulose is

useful to prepare tablet containing poorly

compressible ingredients by direct

compression. The silicification affects the

moisture sorption and the packing during

tapping as well as the particle deformation

during tableting. Prosolv showed slight

increase in the tensile strength but marked

increase in the disintegration time of the

tablets compared to Avicel. It was

demonstrated that the co-processing of

microcrystalline cellulose with colloidal

silicone dioxide has no significant

contribution on the tablet strength of

lubricated tablets containing the physical

mixture of microcrystalline cellulose and

colloidal silicone dioxide. [30]

StarLac:

Starlac is a co-processed excipient consists

of lactose monohydrate and maize starch

produced by spray drying. The advantage

of Starlac are its good flow ability

depending on the spray-drying process, an

acceptable crushing force due to its lactose

content, its rapid disintegration depending

on starch. Gohel and Jogani demonstrated

use of multiple linear regressions in

development of co-processed lactose and

starch. Authors concluded that as the

lactose/starch ratio increased Carr‟s index

of the adjuvant and crushing strength of

the tablets increased while friability

decreased. Percentage of starch paste has

inverse effect on the friability. [31]

REGULATORY PERSPECTIVE:

In the light of the fact that a chemical

change is absent during processing, co-

processed excipients can be considered to

retain the generally regarded as safe

(GRAS) status if the parent excipients are

GRAS certified by the regulatory agencies,

then co-processed excipients are also .This

reduces the requirement for additional

toxicological studies as mandatory for a

new chemical entity seeking regulatory

approval. [31]

A very limited number of co-

processed excipients are included in

pharmacopoeial monographs.



• Microcrystalline Cellulose and

Carboxymethylcellulose Sodium

(USNF) – aka Dispersible Cellulose BP

• Compressible Sugar (USNF) (BP)

• Various acrylate dispersions (Truly co-

processed) (USNF and Ph.Eur)

However the majority of commercially

available co- processed excipients are not

described in a major pharmacopoeia. For

any „new‟ excipient regulatory agencies

should be looking for a safety assessment,

However in the case of co-processed

excipients the components, the

manufacturing process and component

combination are not novel, The only novel

parameters are the physical form and the

functionality. Therefore it should not be

necessary to perform a full toxicological

assessment, It should be possible to

provide data to „bridge‟ to the safety data

of the components, However the bridging

assessment needs to be fully justified by

demonstrating that the co-processing

process does not create a change of

regulatory significance. The absence of

significant chemical change should be

demonstrated using suitable techniques

including:

• Scanning Electron Microscopy

• Pyncnometry

• FT-IR

• 13

C NMR

• X ray diffraction

• Viscosity measurements

• Differential Scanning Calorimetry

The Regulation of Excipients

New excipients are only approved

throughout the world when they are

included in new drug applications. A

separate independent regulatory review

system would greatly enhance the use of

new excipients.

Excipients regulation:

- No independent regulatory

approval process exists for new

excipients

- New excipients are only approved

within a new drug application

approval

- New excipients need supporting

safety data; testing strategy

developed on a case by case Basis;

large investment for safety studies

- Drug product manufacturers are

reluctant to use new excipients;

they generally rely on excipients

already used in approved drug

products

IPEC-Americas have submitted a proposal

for Excipient Master File, analogous to

Drug Master File, to the Food and Drug

Administration. This document is intended

to provide a standard format for submitting

excipient safety and manufacturing

information to regulatory agencies, and

includes provisions for co-processed

excipients also. The major obstacle to the

success of co-processed excipients in the

marketplace is their non-inclusion in

official monographs. The mixture of

excipients was presented as a topic to the

National Formulary and was assigned a

priority on the basis of its use in marketed

dosage forms in which processing

provided added functional value to the

excipient mixture. Although spray-

crystallized dextrose-maltose (EMDEX1,

J. Rettenmaier & Sohne GmbH & Co. KG,

Germany) and compressible sugars are co-

processed, they are commonly considered



as single components and are listed as such

in the United States Pharmacopeia, while

the third edition of the Handbook of

Pharmaceutical Excipients has listed

SMCC as a separate excipient .[1]

Japan Master File Guideline: (enforced

as of April 1st, 2005) [1]

DMF plus Japanese QOS

J DMF consists of open and closed part,

like EU DMFs e-CTD format accepted

Categories of JMFs:

I - API /intermediates used for drugs*

II - New excipients

III - Medical devices

IV - Others (packaging etc.)

European Excipient Master Files

In contrast to Japan, Canada and the US, in

Europe, for materials, where a Certificate

of Suitability is not available, confidential

information needed to support the drug

product filing by a pharmaceutical

manufacturer must be supplied directly to

the drug manufacturer e.g. by using

confidentiality agreements. IPEC Europe

Initiative on Excipient Master Files has

been implemented to meet the need, create

awareness with the EU stakeholders and

authorities (mission statement). [32]

COMMERCIAL STATUS:

Co-processed excipients are widely

available in the market for a wide

spectrum of purposes. Majority of these

are produced mainly by spray drying.

Ludipress is produced by fluidized-bed

granulation, while Di-Pac (American

Sugar Co., New York, U.S.) involves

mini-granulation of sugar crystals glued

together with amorphous dextrin. Some of

the co-processed excipients which are

commercially available in the present

scenario and their brief details are

mentioned in the following table no. 1.

Table No. 1. Commercially available co-processed excipients

Trade name Manufacturer Components Added

advantage

Regulatory

status

IID

limits

Ludipress® BASF Lactose

PVP

Low

hydroscopicity

Good

flowability

Constant tablet

weight

NA 50.73

mg

Ludiflash BASF Mannitol-90%

Crospovidone-5%

Polyvinyl acetate-5%

Fast

disintegration

for Oral

Dispersible

Tablets

NA NA

Avicel® CE- 15 FMC

Biopolymer

MCC

Guar

Less grittiness,

improved tablet

palatability

NA NA

Avicel® RC-581

Avicel® RC-591

FMC

Biopolymer

MCC

Sodium CMC

Viscosity

modifier,

NF, Ph

Eur.

160 mg



Avicel® CL-611 thixotropic

characteristics,

Heat and Freeze

thaw stable,

long self life

stability,

lengthly

hydration times

eliminated,

stable at pH

range 4-11

Pharmatose®

DCL 40

DMV ß-lactose

Lactitol

High

Compressibility

Low lubricant

sensitivity

NA NA

StarLac® Meggle α-Lactose MH

Maize Starch

Good

flowability

USP-NF,

Ph Eur.

NA

ProSolv® JRS MCC

Silicon Dioxide

Better flow, less

sensitivity to

wet granulation,

better tablet

hardness

NF 536.349

mg

Di-Pac® Domino Sucrose

Maltodextrin

For direct

compression,

NF NA

StarCap 1500® Colorcon Maize starch

Pregel Starch

Tablet

disintegration

and

dissolution

independent of

pH

USP,

Ph Eur, JP

482.0

mg

Xylitab® Danisco Xylitol

Sodium CMC

Directly

compressible

NA NA

Celocal® FMC

Biopolymer

MCC

Calcium sulfate

Directly

compressible

NA NA

Vitacel® VE-

650

FMC

Biopolymer

MCC

Calcium carbonate

Direct

compression,

encapsulation

NA NA

LustreClearTM FMC

Biopolymer

MCC

Carrageenan

Efficient Tablet

coating with

short hydration

time prior to

coating and the

first drying time

NA NA



Formaxx® Merck KGaA Calcium carbonate

Sorbitol

High

compressibility,

excellent taste

masking, free

flow, superior

content

uniformity,

controlled

particle size

distribution

NA NA

PharmaburstTM SPI pharma Carbohydrate

system, made from

compendia

ingredients

High

compactibility,

high loading in

small tablets,

smooth mouth

feel, rapid

disintegration

NA 671.13

mg

AdvantoseTM

FS 95

SPI pharma Fructose

Corn Starch

Excellent flow,

good

compressibility,

tablets hold

shape well and

easily chewable.

NA NA

MicroceLac

100

Meggle α-Lactose MH

MCC

Good

flowability

USP-NF,

Ph Eur, JP

614.2

mg

EffersodaTM SPI Pharma Sodium

BiCarbonate-88%

Sodium Carbonate-

12%

Improve the

stability of the

Effervescent

product

NA NA

Sorbcel M® Blanver Mannitol +

Polyethylene glycol

+

Polyvinylpyrrolidone

+ Citric Acid +

Sodium Bicarbonate.

Effervescent

excipients,

Homogeneous

and stable mix

of excipients

that dissolves

completely and

rapidly,

resulting in a

clear solution

free of insoluble

residues.

NA NA

Sorbcel E® Blanver Sorbitol + Mannitol

+

Polyvinylpyrrolidone

+ Citric Acid +

Sodium Bicarbonate.

NA NA

Fujicalin® Fuji Chemical DCP Anhydrous -Directly

compressible,

-High

USP-NF,

Ph Eur, JP

850.0

mg



exceptional

flow

-Rapid

disintegration

Neusilin® Fuji Chemical Amorphous

Magnesium

Aluminometasilicate

-Oils and

extracts to

powder

-Improve flow

-Anti caking

-Improve

Compressibility

-To make Solid

dispersion

USP/NF

JP

NA

F-Melt ® Fuji Chemical Carbohydrate,

Disintegrant, DCP

etc

(Total 5 ingredients)

-Directly

compressible

-Oral

disintegrating

time less than

30 seconds

-Highly

flowable with

minimum or no

sticking/capping

US type IV

DMF filed

on 2007

NA

Sepitrap 80® Seppic Polysorbate 80 -Improves the

bioavailability

of APIs with

low solubility

-It can be used

in direct

compression

processes.

NA NA

Sepitrap 4000® Seppic Ethoxylated

hydrogenated castor

oil

NA NA

TAP -400® Pharmatrans Processed Tartaric

acid pellets

As a acidic core

for drug

delivery

technologies

NA NA

Conclusion:

At present no regulatory mechanism exists

in which a new excipient can be assessed

entirely for safety and quality. Therefore,

the pharmaceutical industry has been

reluctant to use new excipients, which in

turn could prevent the advancement of

pharmaceutical technology. The

implementation of a global DMF system to

handle confidential information for

excipients may support efforts for an



independent acknowledgement and review

system for new excipients.

New excipients could be evaluated with a

base set of data for general acceptance

similar to the programs established by the

Flavour and Extract Manufacturers

Association for flavour ingredients and the

Cosmetic Ingredient Review for cosmetic

ingredients. However, the use of a new

excipient still would be subject to final

approval as part of a drug product, and

specific-use information would be supplied

with the drug product submission.

Co-Processed excipients certainly have a

role in pharmaceutical innovation. They

can be custom designed to possess specific

characteristics and functionality for

specific applications. Co-Processing does

create a new entity. But demonstration of

the lack of significant chemical change

should allow entry to market much faster

(and more cost effectively) than with a

truly novel chemical or biological

excipient.

REFERENCES:

1. Hebestreit Philipp Dr. Pharma

Ingredients & Services, BASF,

Addressing specific regulatory

excipient requirements in the

marketing authorization, PharmSci

Fair Nice, June 11th, 2009.

2. Moreton A, Lawrence H. Block,

Richard C. Co-processed Excipients: in

Pharmacopieal Forum. 2009.

3. Dev KM. Co processed

Microcrystalline Cellulose and Calcium

Carbonate and Its Preparation, US

Patent No. 4,744,987 to FMC

Corporation (Philadelphia, PA), 1988.

4. Bolhius GK, Chowhan ZT. Materials

for Direct Compaction, in

Pharmaceutical Powder Compaction

Technology, G. Alderborn and C.

Nystrom, Eds. (Marcel Dekker Inc.,

New York, NY,), (1996), pp.419–500.

5. Carl Mroz (June.2009), IPEC Europe,

Co-Processed Excipients: Regulatory

Challenges Colorcon Limited.

6. Gupta Piyush, Nachaegari Satish K,

Bansal Arvind K. Improved Excipient

Functionality by Co-processing, and.

pp.109-112.

7. Reimerdes D. the near future of tablet

excipients. Manuf Chemist 1993;

64:14–15.

8. Badwe N, Sharma N. The blend was

compressed into tablets using 11.2 mm

FFBE punch on a 10 station rotary

machine Eastern Pharmacist 1996; 41:

33.

9. Modliszewski JJ, Ballard DA.

Coprocessed Galctomannan–

Glucomannan, US Patent No.

5,498,436, FMC Corporation

(Philadelphia, PA) 1996.

10. Tobyn MJ, McCarthy GP, Staniforth

JN, Edge S. Physicochemical

comparison between microcrystalline

cellulose and silicified

microcrystalline cellulose. Int J Pharm

1998; 169:183–194.

11. Marshall K. Compression and

consolidation of powdered solids. In:

Lachman L, Lieberman HA, Kanig JL

eds. The Theory and Practice of

Industrial Pharmacy. Bombay:

Varghese Publishing House, 1986:66–

99.

12. Maarschalk KVDV, Bolhuis GK.

Improving properties of materials for



direct compaction Pharm Technol

1999; 23:34–46, 96.

13. Bolhius GK, Chowhan ZT. Materials

for Direct Compaction, in


Technology, G. Alderborn and C.

Nystrom Eds. (Marcel Dekker Inc.,

New York, NY, 1996), pp.419–500.

14. Allen JD. Improving direct

compression with SMCC, Manuf.

Chemist 1996; 67:19–23.

15. York P. Crystal engineering and

particle design for the powder

compaction process, Drug Dev Ind

Pharm, 1992; 18:677–721.

16. Belda PM, Mielck JB. The tableting

behavior of Cellactose compared with

mixtures of celluloses with lactoses,

Eur J Pharm Biopharm 1996; 42:325–

330.

17. Schmidt PC, Rubensdorfer CJW.

Evaluation of Ludipress as a

„„multipurpose excipient‟‟ for direct

compression. Part I: powder

characteristics and tableting

properties. Drug Dev Ind Pharm 1994;

20:2899–2925.

18. Joshi V. Excipient choice in solid

dosage forms. Drug Deliv Technol

2002; 2(6):36–40.

19. Flores LE, Arellano RL, Esquivel JJD.

Study of load capacity of Avicel PH-

200 and Cellactose, two direct

compression excipients, using

experimental design. Drug Dev Ind

Pharm 2000; 26:465–469.

20. Sherwood BE, Becker JW. A New

Class of High Functionality

Excipients: Silicified Microcrystalline

Cellulose, Pharm. Technol. 22 (10),

78–88 (1988).

21. Maarschalk KVDV, Bolhuis GK.

Improving properties of materials for

direct compaction, Pharm Technol

1999; 23:34–46, 96.

22. Joshi AA, Duriez X. Added

functionality excipients: an answer to

challenging formulations, Pharm

Technol (Excipients and Solid Dosage

Forms) 2004:12–19.

23. Product Information Brochure, SPI

Polyols, France, 1999.

24. Plaizier-Vercammen, JA, Van Den

Bossche H. Evaluation of the

Tableting Properties of a New

Excipient for Direct Compression,

Pharm. Ind., 54:973-977, 1992.

25. Monedero Perales MC, Munoz-Ruiz,

Velasco A, Antequera MV, Jimenez-

Castellanos MR. Study of the

Compaction Mechanisms of Lactose-

Based Direct Compression Excipients

Using Indentation Hardness and

Heckel plot, J. Pharm. Pharmacol.,46:

177-181, 1994.

26. Garr JS, Rubinstein MH. Compaction

Properties of a Cellulose-Lactose

Direct Compression Excipient, Pharm.

Tech. Int., 3: 24-27, 1991.

27. Plaizier-Vercammen, JA, Van Den

Bossche H. Evaluation of the

Tableting Properties of a New

Excipient for Direct Compression,

Drugs Made in Germany, 36: 133-

137, 1993.

28. Gohel MC, Pranav D. Jogani. A

review of co-processed directly

compressible excipients. Journal of

pharmacy pharmaceutical sciences,

Volume: 8, Issue: 1, Pages: 76-93,

2005.



29. Bolhuis GK, Chowhan ZT. Materials

for Direct Compression,


Technology, Vol-7, Marcel Dekker,

USA, 419-499, 1996.

30. Moreton RC. Tablet excipients to the

year 2001: a look into the crystal ball.

Drug Dev Ind Pharm 22:11–23, 1996.

31. Moreton RC. Cellulose, silicified

microcrystalline. In: Kibbe AH ed.

Handbook of Pharmaceutical

Excipients. Washington, D.C.:

American Pharmaceutical Association

and London: Pharmaceutical Press,

2000:110–111.

32. Christopher C. DeMerlis. The IPEC-

Americas Excipient Master File

Guide, Pharma. Tech., June 2002.

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